Howard P. Goodkin

Gaps and opportunities in refractory status epilepticus research in children: A multi-center approach by the Pediatric Status Epilepticus Research Group (pSERG)

Purpose: Status epilepticus (SE) is a life-threatening condition that can be refractory to initial treatment. Randomized controlled studies to guide treatment choices, especially beyond first-line drugs, are not available. This report summarizes the evidence that guides the management of refractory convulsive SE (RCSE) in children, defines gaps in our clinical knowledge and describes the development and works of the ‘pediatric Status Epilepticus Research Group’ (pSERG). Methods: A literature review was performed to evaluate current gaps in the pediatric SE and RCSE literature. In person and online meetings helped to develop and expand the pSERG network. Results: The care of pediatric RCSE is largely based on extrapolations of limited evidence derived from adult literature and supplemented with case reports and case series in children. No comparative effectiveness trials have been performed in the pediatric population. Gaps in knowledge include risk factors for SE, biomarkers of SE and RCSE, second-and third-line treatment options, and long-term outcome. Conclusion: The care of children with RCSE is based on limited evidence. In order to address these knowledge gaps, the multicenter pSERG was established to facilitate prospective collection, analysis, and sharing of de-identified data and biological specimens from children with RCSE. These data will allow identification of treatment strategies associated with better outcomes and delineate evidence-based interventions to improve the care of children with SE.

Current practices of the child neurologist in managing sports concussion.

Given the 2010 position statement issued by the American Academy of Neurology that neurologists be consulted on return-to-play decisions following a concussion, we surveyed members of the Child Neurology Society to asses clinical practice management of concussion among child neurologists. Among the 239 respondents, the majority continued to rely on the American Academy of Neurology’s 1997 Practice Parameter to guide their decision-making process. Although the 2008 consensus statement from the Third International Conference on Concussion in Sport (Zurich Guidelines) is currently considered the most up-to-date guideline, few respondents relied exclusively on this guideline. More respondents who completed continuing medical education on concussion reported making clinical decisions based on the Zurich guidelines. The finding that child neurologists who completed continuing medical education had a greater familiarity with the more recently proposed consensus-based concussion guidelines supports the development of additional education in sports concussion at all levels of child neurology training.

Acute encephalopathy with biphasic seizures and late restricted diffusion on MRI in a Japanese child living in the USA

We report an 18‐month‐old Japanese female living in the USA whose clinical course and radiographic findings were consistent with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). She was initially diagnosed with complex febrile seizures. However, on day 3 of admission, she had a cluster of complex partial seizures and the onset of a global developmental regression. In contrast to the normal magnetic resonance image of the brain obtained on admission, subsequent imaging demonstrated transient subcortical diffusion‐weighted abnormalities in the white matter of the bilateral posterosuperior frontal, parietal, temporal, and occipital regions, with sparing of the perirolandic area. One year later, her developmental delay, although improved, persisted and she continued to experience sporadic seizures while being treated with topiramate monotherapy. Repeat imaging showed diffuse, poorly defined, increased T2 signals in the white matter of the posterosuperior frontal, parietal, temporal and occipital regions and diffuse cerebral volume loss. Previous reports of AESD have been limited to children aged under 4 years living in Japan. With the identification of this case, it is important that all physicians, not only those in Japan, who care for children with febrile seizures be aware of AESD and its associated neurological morbidity.

Association of Time to Treatment With Short-term Outcomes for Pediatric Patients With Refractory Convulsive Status Epilepticus.

Importance Treatment delay for seizures can lead to longer seizure duration. Whether treatment delay is associated with major adverse outcomes, such as death, remains unknown. Objective To evaluate whether untimely first-line benzodiazepine treatment is associated with unfavorable short-term outcomes. Design, Setting, and Participants This multicenter, observational, prospective cohort study included 218 pediatric patients admitted between June 1, 2011, and July 7, 2016, into the 11 tertiary hospitals in the United States within the Pediatric Status Epilepticus Research Group. Patients, ranging in age from 1 month to 21 years, with refractory convulsive status epilepticus (RCSE) that did not stop after the administration of at least 2 antiseizure medications were included. Patients were divided into 2 cohorts: those who received the first-line benzodiazepine treatment in less than 10 minutes and those who received it 10 or more minutes after seizure onset (untimely). Data were collected and analyzed from June 1, 2011, to July 7, 2016. Main Outcomes and Measures The primary outcome was death during the related hospital admission. The secondary outcome was the need for continuous infusion for seizure termination. Multivariate analysis of mortality controlled for structural cause, febrile RCSE, age, and previous neurological history (including previous RCSE events). Use of continuous infusions was additionally adjusted for generalized RCSE, continuous RCSE, and 5 or more administrations of antiseizure medication. Results A total of 218 patients were included, among whom 116 (53.2%) were male and the median (interquartile range) age was 4.0 (1.2-9.6) years. The RCSE started in the prehospital setting for 139 patients (63.8%). Seventy-four patients (33.9%) received their first-line benzodiazepine treatment in less than 10 minutes, and 144 (66.1%) received untimely first-line benzodiazepine treatment. Multivariate analysis showed that patients who received untimely first-line benzodiazepine treatment had higher odds of death (adjusted odds ratio [AOR], 11.0; 95% CI, 1.43 to ∞; Pu2009=u2009.02), had greater odds of receiving continuous infusion (AOR, 1.8; 95% CI, 1.01-3.36; Pu2009=u2009.047), had longer convulsive seizure duration (AOR, 2.6; 95% CI, 1.38-4.88; Pu2009=u2009.003), and had more frequent hypotension (AOR 2.3; 95% CI, 1.16-4.63; Pu2009=u2009.02). In addition, the timing of the first-line benzodiazepine treatment was correlated with the timing of the second-line (95% CI, 0.64-0.95; Pu2009<u2009.001) and third-line antiseizure medications (95% CI, 0.25-0.78; Pu2009<u2009.001). Conclusions and Relevance Among pediatric patients with RCSE, an untimely first-line benzodiazepine treatment is independently associated with a higher frequency of death, use of continuous infusions, longer convulsion duration, and more frequent hypotension. Results of this study raise the question as to whether poor outcomes could, in part, be prevented by earlier administration of treatment.

An unusual presentation of anti-Hu-associated paraneoplastic limbic encephalitis.

Paraneoplastic limbic encephalitis is a rare disorder characterized by personality changes, seizures, memory loss, and psychiatric symptoms often associated with antineuronal antibodies. It is well described in the adult literature but is still underreported in the pediatric literature. Symptoms are usually multifocal and subacute in presentation, occurring over days to weeks; however, in rare cases, symptom onset can be more gradual. We report the case of a 9‐year‐old male with anti‐Hu‐associated paraneoplastic limbic encephalitis that presented as episodic ataxia and behavioral changes evolving to intractable epilepsy and worsening behavioral changes over the course of a year. This case highlights the importance of considering a paraneoplastic disorder in the differential diagnosis for unexplained multifocal neurological symptoms of subacute or chronic onset as earlier detection and treatment may result in an improved outcome.

Phosphatase inhibition prevents the activity‐dependent trafficking of GABAA receptors during status epilepticus in the young animal

To determine if the activity‐dependent trafficking of γ2 subunit–containing γ‐aminobutyric acid type A receptors (GABAARs) that has been observed in older animals and posited to contribute to benzodiazepine pharmacoresistance during status epilepticus (SE) is age‐dependent, and to evaluate whether blockade of protein phosphatases can inhibit or reverse the activity‐dependent plasticity of these receptors.

The pervasive reduction of GABA-mediated synaptic inhibition of principal neurons in the hippocampus during status epilepticus.

The goal of this study was to determine whether there are region-specific or time-dependent changes in GABA-mediated synaptic inhibition of principal neurons in the hippocampus during in vivo status epilepticus. Standard whole cell patch clamp electrophysiological techniques were used to characterize miniature inhibitory postsynaptic currents (mIPSCs) in recordings from the principal neurons (PNs) of the dentate gyrus, CA1, and CA3 in acutely-obtained hippocampal slices from control and lithium/pilocarpine-induced status epilepticus(SE)-treated animals. The reduction in mIPSC amplitude was pervasive across the 3 regions examined in hippocampal slices obtained after 60 min (late) or just 15 min after the onset of SE. The mIPSC frequency was reduced in all 3 regions after 60 min and 2 regions (dentate, CA1) after 15 min. These findings lend further support to the hypothesis that a rapid modification of the postsynaptic GABAA receptor population leads to a widespread decline in GABA-mediated inhibition that, in part, contributes to both the self-sustaining nature of SE and to the decrease in the efficacy of benzodiazepines.

Extrapontine Myelinolysis Resulting in Transient Cortical Blindness

Central pontine myelinolysis and extrapontine myelinolysis are characterized by symmetric demyelination subsequent to rapid shifts in serum osmolality. Described here is a novel case of transient cortical blindness in association with imaging features of extrapontine myelinolysis, which occurred in a child with carbamoyl phosphate synthetase deficiency after rapid correction of hyperammonemia. Serum sodium levels were within normal limits at presentation and throughout the period of ammonia correction. A potential pathogenic mechanism of osmotic demyelination in the setting of acute treatment for hyperammonemia in a patient with a urea cycle abnormality includes disruption of the blood-brain barrier and re-equilibration of organic osmolytes, particularly glutamine.

Efficacy and safety of ketogenic diet for treatment of pediatric convulsive refractory status epilepticus

PURPOSEnTo describe the efficacy and safety of ketogenic diet (KD) for convulsive refractory status epilepticus (RSE).nnnMETHODSnRSE patients treated with KD at the 6/11 participating institutions of the pediatric Status Epilepticus Research Group from January-2011 to December-2016 were included. Patients receiving KD prior to the index RSE episode were excluded. RSE was defined as failure of ≥2 anti-seizure medications, including at least one non-benzodiazepine drug. Ketosis was defined as serum beta-hydroxybutyrate levels >20u202fmg/dl (1.9u202fmmol/l). Outcomes included proportion of patients with electrographic (EEG) seizure resolution within 7u202fdays of starting KD, defined as absence of seizures and ≥50% suppression below 10u202fμV on longitudinal bipolar montage (suppression-burst ratio ≥50%); time to start KD after onset of RSE; time to achieve ketosis after starting KD; and the proportion of patients weaned off continuous infusions 2 weeks after KD initiation. Treatment-emergent adverse effects (TEAEs) were also recorded.nnnRESULTSnFourteen patients received KD for treatment of RSE (median age 4.7 years, interquartile range [IQR] 5.6). KD was started via enteral route in 11/14 (78.6%) patients. KD was initiated a median of 13u202fdays (IQR 12.5) after the onset of RSE, at 4:1 ratio in 8/14 (57.1%) patients. Ketosis was achieved within a median of 2u202fdays (IQR 2.0) after starting KD. EEG seizure resolution was achieved within 7u202fdays of starting KD in 10/14 (71.4%) patients. Also, 11/14 (78.6%) patients were weaned off their continuous infusions within 2 weeks of starting KD. TEAEs, potentially attributable to KD, occurred in 3/14 (21.4%) patients, including gastro-intestinal paresis and hypertriglyceridemia. Three month outcomes were available for 12/14 (85.7%) patients, with 4 patients being seizure-free, and 3 others with decreased seizure frequency compared to pre-RSE baseline.nnnCONCLUSIONSnThis series suggests efficacy and safety of KD for treatment of pediatric RSE.

Loss of CLOCK Results in Dysfunction of Brain Circuits Underlying Focal Epilepsy.

Because molecular mechanisms underlying refractory focal epilepsy are poorly defined, we performed transcriptome analysis on human epileptogenic tissue. Compared with controls, expression of Circadianxa0Locomotor Output Cycles Kaput (CLOCK) is decreased in epileptogenic tissue. To define the function of CLOCK, we generated and tested thexa0Emx-Cre; Clockflox/flox and PV-Cre; Clockflox/flox mouse lines with targeted deletions of the Clock gene in excitatory and parvalbumin (PV)-expressing inhibitory neurons, respectively. The Emx-Cre; Clockflox/flox mouse line alone has decreased seizure thresholds, but no laminar or dendritic defects in the cortex. However, excitatory neurons from the Emx-Cre; Clockflox/flox mouse have spontaneous epileptiform discharges. Both neurons from Emx-Cre; Clockflox/flox mouse and human epileptogenic tissue exhibit decreased spontaneous inhibitory postsynaptic currents. Finally, video-EEG of Emx-Cre; Clockflox/flox mice reveals epileptiform discharges during sleep and also seizures arising from sleep. Altogether, these data show that disruption of CLOCK alters cortical circuits and may lead to generation of focal epilepsy.